Osteoclasts Control Re-activation of Dormant Myeloma Cells by Remodeling the Endosteal Niche

Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and re-populate the tumor. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and re-activation. In this study we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state which is switched ‘on’ by engagement with bone lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodeling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy targeting dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse. Affymetrix microarray was performed on dormant, proliferating and transitioning multiple myeloma cells extracted ex vivo. GFP expressing 5TGM1 multiple myeloma cells were labelled with a DiD membrane label and its retention of DiD (DiDHigh) discriminates dormant from proliferating cells (DiDNeg). At 28 days post intravenous injection, cells were extracted from the bone marrow of C57BLkALwRij mice using FACS and RNA was extracted.